The present invention relates to a 2,4,6-substituted phenol derivatives which can be utilized in the medical field. More particularly, the present invention relates to a 2,4,6-substituted phenol having both HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitory activity and antioxidation action. The derivatives are useful as antiatherosclerotic agents, antilipemic agents and agents for preventing the progress of arteriosclerosis. Besides, the above-mentioned 2,4,6-substituted phenols have inhibitory action on ulcer formation and the like relating to antioxidation action and antiinflammatory action and the like relating to action for preventing cytotoxicity and lipoxygenase inhibitory action. Accordingly, the substituted phenol derivatives can be used as an antiangiopathic agent, an antiasthmatic agent, an antidiabetic agent, an antiulcer agent, an antiinflammatory agent, an antineoplastic agent, an antiallergic agent or the like.
Atherosclerosis is regarded to be the incipient process of arteriosclerosis which is caused by depositing lipids containing cholesterol as a primary component in intimae of aortas and arteries, hyperplasia of arterial walls in company with the deposition and hyperplasia of connective tissue, and hardening.
Factors relating to the onset of atherosclerosis are never simple. Until now, hypertension, lipemia, excessive smoking, obesity, diabetes, hyperuricemia, stress, heredity, lack of exercise and the like have been exemplified, as dangerous factors of atherosclerosis. It is considered that atherosclerosis is caused by piling these dangerous factors for a long time. Among them, behavior of cholesterol which exists as LDL in blood is particularly noticed. In particular, accumulation of cholesterol on arterial walls resulting from incorporation of the oxidized LDL into macrophages in arterial walls is important. The resulting accumulation causes angiopathy. On the other hand, it has been considered that development of atherosclerosis is accelerated by various factors such as increase of cholesterol in blood in association with disturbance in incorporation of LDL into liver and cacochymia of LDL in liver, hydrodynamic condition of blood in association with physical change of blood and red blood cell, damage of endothelial cells, physiological or pathologic hypertrophy of arterial walls and decrease in utilization of lipids in tissue of arteries.
Hitherto, in drug therapy of atherosclerosis, antiatherosclerotic agents such as pyridinol carbamate, agents for lowering lipids, such as clofibrate, nicotinic acid, .alpha.-thyroxine and cholestyramin, and inhibitory agents on platelet aggregation, such as dipyridamole and aspirin, have been used as agents relating to such complicated.
There are two methods of interest in lowering the lipids content in serum. The first method is preventing the oxidation and denaturation of LDL. In this method, compounds having a structure of 2,4,6-substituted phenol are used. Such compounds are, for instance, disclosed in U.S. Pat. Nos. 4,029,812, 4,076,841, 4,078,084, European Patent No 273451 and the like. The second method utilizes the inhibitory action of HMG-CoA CoA reductase. This method which comprises inhibiting the biosynthesis of cholesterol from acetic acid in the body is considered to be effective against the onset of atherosclerosis and in therapy of atherosclerosis. Nakatani discloses that Mevastatin, Pravastatin, Lovastatin and Simarastatin inhibit cholesterol synthesis, and suggests the posibility that a compound having HMG-CoA reductase inhibitory activity can be applied as an antiarterioscelorotic agent and an antilipemic agent (See Farmashia, Kusuri no kaisetsu,
HMG-CoA reductase inhibitor, 24, number 12, pages 1217-1219, 1988).
As is clear from the above description, it is considered that inhibition of cholesterol synthesis and cholesterol incorporation into macrophages by preventing oxidation and denaturation of LDL are important for prevention and treatment of atherosclerosis. The development of medicaments useful in both of the above described methods has been desired.
As the result of the continuous effort of the present inventors, they have designed a 2,4,6-substituted phenol having both antioxidation activity and HMG-CoA reductase inhibitory activity. The present invention is based upon these finding.
As structurally similar compounds to the compound of the present invention, those described in U.S. Pat. No. 4,801,611, Japanese Unexamined Patent Publication No. 6653/1985, Japanese Unexamined Patent Publication No. 158164/1985 and Japanese Unexamined Patent Publication No. 38086/1989, and Probucol having the formula: ##STR3## are exemplified. However, there is no satisfiable compound having both antioxidation activity and simultaneously, HMG-CoA reductase inhibitory activity as the compounds of the present invention exhibit.
It is an object of the present invention to provide a 2,4,6-substituted phenol having both antioxidation activity and HMG-CoA reductase inhibitory activity at the same time or a pharmaceutically acceptable salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising the same or a pharmaceutically acceptable salt thereof as an effective ingredient, in association with a pharmaceutically acceptable substantially nontoxic carrier or excipient.
It is a still further object of the present invention to provide a useful pharmaceutical composition for lipemia comprising the same or a pharmaceutically acceptable salt thereof.
These and the other objects of the present invention will become apparent from the description hereinafter.